Numerical Analysis of Respiratory Aerosol Deposition: Effects of Exhalation, Airway Constriction and Electrostatic Charge

The dynamics of particle laden flows are integral to the analysis of toxic particle deposition and medical respiratory aerosol delivery. Computational fluid-particle dynamics (CFPD) can play a critical role in developing a better understanding of particle laden flows, especially in a number of under-explored areas. The applications considered in this study include both the numerical aspects and the physical phenomena of respiratory aerosol transport. Objective I: Considering the effects of mesh type and grid convergence, four commonly implemented mesh styles were applied to a double bifurcation respiratory geometry and tested for flow patterns and aerosol deposition. Results indicated that the mesh style employed had a significant effect on the transport and deposition of aerosols with hexahedral meshes being most accurate. Objective II: In order to evaluate the effects of bronchoconstriction under exhalation conditions, normal and constricted pediatric airway models were considered. Results include (i) a significant increase in deposition for constricted airways, and (ii) a novel correlation for deposition during exhalation based on the Dean and Stokes numbers. Objective IIIa: Considering evaluation of an aerosol size sampler, an eight-stage Andersen cascade impactor (ACI) was numerically analyzed. The numerical simulations indicated high non-uniformity and recirculation in the flow field. Numerical predictions of retention fraction matched well with existing experiments (0.5 11% error). Objective IIIb: As an extension to this study, numerical predictions of electrostatic charge effects on aerosol transport and deposition in the ACI were presented. Charges consistent with standard pharmaceutical pressurized metered dose inhalers and dry powder inhalers were considered. The numerical predictions indicated that charged aerosols deposit as if they were 5 85% larger due to electrostatic effects. Applications of the studies considered include (i) quantitative guidance in selecting numerical mesh styles and development of standard grid convergence criteria, (ii) the development of more accurate whole-lung deposition models that better evaluate exhalation conditions,(iii) improvements in the design of pharmaceutical assessment and delivery devices, and (vi) correction values to account for electrostatic charge on pharmaceutical aerosols

Effect of high-dose N-acetylcysteine on airway geometry, inflammation, and oxidative stress in COPD patients

Background: Previous studies have demonstrated the potential beneficial effect of N-acetylcysteine (NAC) in chronic obstructive pulmonary disease (COPD). However, the required dose and responder phenotype remain unclear. The current study investigated the effect of high-dose NAC on airway geometry, inflammation, and oxidative stress in COPD patients. Novel functional respiratory imaging methods combining multislice computed tomography images and computer-based flow simulations were used with high sensitivity for detecting changes induced by the therapy. Methods: Twelve patients with Global Initiative for Chronic Obstructive Lung Disease stage II COPD were randomized to receive NAC 1800 mg or placebo daily for 3 months and were then crossed over to the alternative treatment for a further 3 months. Results: Significant correlations were found between image-based resistance values and glutathione levels after treatment with NAC (P = 0.011) and glutathione peroxidase at baseline (P = 0.036). Image-based resistance values appeared to be a good predictor for glutathione peroxidase levels after NAC (P = 0.02), changes in glutathione peroxidase levels (P = 0.035), and reduction in lobar functional residual capacity levels (P = 0.00084). In the limited set of responders to NAC therapy, the changes in airway resistance were in the same order as changes induced by budesonide/formoterol. Conclusion: A combination of glutathione, glutathione peroxidase, and imaging parameters could potentially be used to phenotype COPD patients who would benefit from addition of NAC to their current therapy. The findings of this small pilot study need to be confirmed in a larger pivotal trial

The effects of extrafine beclometasone/formoterol (BDP/F) on lung function, dyspnea, hyperinflation, and airway geometry in COPD patients: novel insight using functional respiratory imaging

Background: The efficacy of inhaled corticosteroids (ICS) in moderately severe COPD patients remains unclear. At the same time, the use of extrafine particles in COPD patients is a topic of ongoing research. Objectives: This study assessed the effect of ICS in steroid-naive mild COPD patients and the effect of reducing the ICS dose in more severe COPD patients previously using ICS when switching to an extrafine particle BDP/F formulation (Foster using Modulite technology, Chiesi Pharmaceutici, Parma, Italy). Methods: Novel functional respiratory imaging (FRI) methods, consisting of multi-slice CT scans and Computational Fluid Dynamics, were used in combination with conventional pulmonary function tests and patient reported outcomes. Results: The study showed that the administration of extrafine BDP/F after 4-6 h led to a significant improvement in lung function parameters and hyperinflation as determined by spirometry, body plethysmography, and functional respiratory imaging. After 6 months of treatment, it was observed that, compared to baseline, the hyperinflation on lobar level at total lung capacity was significantly reduced (-1.19 +/- 7.19 %p, p=0.009). In addition, a significant improvement in SGRQ symptom score was noted in the entire patient population. Patients who improved in terms of hyperinflation also improved their MMRC dyspnea score. CFD indicated a difference in regional deposition between extrafine and non-extrafine formulations with -11% extrathoracic deposition and up to +4% lobe deposition for the extrafine formulation. Conclusions: The study showed that the administration of extrafine BDP/F improved lung function parameters and hyperinflation. Patients previously treated with ICS remained stable despite the lower dose, while ICS naive patients improved in terms of lobar hyperinflation. FRI seems to be a sensitive biomarker to detect clinically relevant changes that are not detected by spirometry. The next step is to confirm these findings in a controlled trial

A case series on lung deposition analysis of inhaled medication using functional imaging based computational fluid dynamics in asthmatic patients: effect of upper airway morphology and comparison with in vivo data

Context: Asthma affects 20 million Americans resulting in an economic burden of approximately $18 billion in the US alone (Allergies and Asthma Foundation 2000; National Center for Environmental Health (NCEH) 1999). Research studies based on differences in patient-specific airway morphology for asthma and the associated effect on deposition of inhaled aerosols are currently not available in the literature. Therefore, the role of morphological variations such as upper airway (extrathoracic) occlusion is not well documented. Objective: Functional imaging based computational fluid dynamics (CFD) of the respiratory airways for five asthmatic subjects is performed in this study using computed tomography (CT) based patient-specific airway models and boundary conditions. Methods: CT scans for 5 asthma patients were used to reconstruct 3D lung models using segmentation software. An averaged inhalation profile and patient-specific lobar flow distribution were used to perform the simulation. The simulations were used to obtain deposition for BDP/Formoterol (R) HFA pMDI in the patient-specific airway models. Results: The lung deposition obtained using CFD was in excellent agreement with available in vivo data using the same product. Specifically, CFD resulted in 30% lung deposition, whereas in vivo lung deposition was reported to be approximately 31%. Conclusion: It was concluded that a combination of patient-specific airway models and lobar boundary conditions can be used to obtain accurate lung deposition estimates. Lower lung deposition can be expected for patients with higher extrathoracic resistance. Novel respiratory drug delivery devices need to accommodate population subgroups based on these morphological and anatomical differences in addition to subject age

A subject-specific fluid-structure interaction model of a lower airway using the nonrigid coherent point drift algorithm

Modeling human breathing using Fluid-Structure Interaction (FSI) is a challenging topic. Performing this in a subject-specific way is almost impossible as tissue properties and muscle interactions are very complex and vary a lot inter- and intra-subject. However, the problem can be inversed if the airway movement is known. Imaging modalities such as high resolution computed tomography (HRCT) scans make it possible to make a detailed anatomical model of the subject's airways. A HRCT at functional residual capacity (FRC) and at total lung capacity (TLC) gives the initial and the final geometry of a breathing cycle. Mapping the nodes of the TLC mesh to the nodes of the FRC mesh using a point set registration algorithm gives the transformation matrix of every node, resulting in a moving mesh which steers the flow. In this study, the nonrigid Coherent Point Drift Algorithm (CPD) is used. In CPD, the alignment of two node sets is considered as a probability density estimation problem and the Gaussian mixture model centroids (representing the TLC node set) is fitted to the FRC node set by maximizing the likelihood. Lower airway models of a healthy subject are reconstructed until the first generation of segmental airways at both TLC and FRC. The FRC model is then mapped to the TLC model using CPD. The volume difference between the mapped and the original model is 0.375% and the root mean square Hausdorff distance is 0.21mm. This initial study shows that CPD is a promising method in modeling the breathing movement